Highlights from Recent Cancer Literature
Journal: Cancer Research (2013)

Tabernero J, Shapiro G, LoRusso P, Cervantes A, Schwartz GK, Weiss GJ, et al. First-in-humans trial of an RNA interference therapeutic targeting VEGF and KSP in cancer patients with liver involvement. Cancer Discov 2013;3:406–17.The use of RNA interference (RNAi) to specifically silence genes involved in cancer pathogenesis holds promise for a new class of therapeutics. The RNAi pathway is present in all mammalian cell types, raising the challenge of designing and delivering highly specific gene silencing to enhance efficacy and also minimize toxicity. Tabernero and colleagues conducted a phase I study of a novel, first-in-class lipid nanoparticle (LNP) containing siRNAs targeting VEGF and kinesin spindle protein (KSP, KIF11) in heavily pretreated patients (n = 41) with refractory cancer, the majority of whom had both hepatic and extrahepatic tumors. Among patients who were evaluable for response (n = 37), 3 had prolonged stable disease control and 1 patient with endometrial cancer and multiple hepatic metastases had a complete and sustained response. The adverse event profile with this therapy consisted primarily of infusion reactions likely to be complement mediated, transient cytokine induction at higher doses despite chemical modification of the LNPs to minimize immunostimulation, and transient thrombocytopenia. One instance of fatal hepatotoxicity was reported in a patient with substantial hepatic tumor burden who had undergone prior partial hepatectomy and splenectomy. A notable finding of the study was the detection of siRNAs in the liver and extrahepatic tumor biopsies, confirming localization to the tumor and providing proof-of-mechanism for RNAi therapeutics in humans. In addition, substantially decreased blood flow in liver tumors was seen by dynamic MRI imaging in nearly half of patients, further supporting changes in VEGF mRNA. Additional studies are required to demonstrate target mRNA downregulation and to establish correlations with clinical outcome.Sadanandam A, Lyssiotis CA, Homicsko K, Collisson EA, Gibb WJ, Wullschleger S, Ostos LC, et al. A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat Med 2013 Apr 14. [Epub ahead of print].De Sousa E Melo F, Wang X, Jansen M, Fessler E, Trinh A, de Rooij LP, et al. Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions. Nat Med 2013 Apr 14. [Epub ahead of print].Colorectal cancer is a clinically diverse disease and a major cause of cancer death. Molecular heterogeneity leads to the challenge of identifying patient subgroups that show responsiveness to specific therapeutic agents. Two companion articles from Nature Medicine explore gene expression data and follow-up experimental evidence to identify clinically relevant subtypes. Sadanandam and colleagues examined gene expression profiles from over 1,000 colorectal cancer tumor samples using consensus-based unsupervised clustering. Because a subset of 80 patients had received a targeted agent (the anti-EGFR receptor agent cetuximab), the authors were able to correlate the results of their clustering analysis with clinical response. Overall, they identified 6 colorectal cancer subtypes. Three subtypes were shown to exhibit better disease-free survival after surgical resection, which appeared to correlate with poor response to cetuximab. However, molecular data suggest that MET inhibitors could be effective therapeutic agents for one of these subtypes. An additional 2 subtypes showed poor-to-intermediate disease-free survival, and these findings were correlated with improved response to chemotherapy. In the second article, Melo and colleagues report on their use of a partially overlapping sample set of expression array data; they defined 3 main colon cancer subtypes (CCS). These authors likewise identified clinical relevance in their classification, as one subgroup (CCS3) showed worse outcome in comparison with the others. Additionally, the CCS3 subgroup was associated with poor response to cetuximab in a manner that was independent of KRAS mutation status (a known marker of poor cetuximab response). Examination of CCS3 showed an overrepresentation of BRAF-mutant tumors as well as tumors that were microsatellite stable and positive for the CpG island methylator phenotype. This subtype is known to develop from a serrated adenoma precursor, in contrast with tubular adenomas. The authors validate this finding by showing that gene expression signatures from serrated adenomas are significantly related to those from CCS3 tumors. Furthermore, they show that CCS3 tumors overexpress markers of the epithelial–mesenchymal transition (EMT), including matrix-remodeling genes. In fact, EMT and matrix genes were upregulated in premalignant serrated lesions, suggesting that CCS3 tumors were primed early for aggressiveness and potential early metastatic behavior. These articles present the use of large sample sets of colorectal tumors to uncover details regarding aggressive biology and identify candidate clinical subsets potentially sensitive to targeted therapeutics. If the data from these reports are validated prospectively, these studies could lead to better personalized care for patients.Lujambio L, Akkari L, Simon J, Grace D, Tschaharganeh DF, Bolden JE, et al. Non-cell-autonomous tumor suppression by p53. Cell 2013;153:449–60.The tumor suppressor p53 (TP53) is central to cellular stress responses induced by DNA damage and oncogene activation. p53 can also limit malignant progression by making damaged cells senescent. Senescent epithelial cells influence their microenvironment by secreting a number of extracellular matrix proteins and degrading enzymes, immune modulators, and inflammatory cytokines. Until now, the activities of p53 in damaged cells were thought to be central to its tumor suppressor activities. Lujambio and colleagues show that p53 also has actions on other cells of the tumor microenvironment, at least in the context of cancer-inducing liver damage. They found that ablation of a p53-dependent senescence program in nonmalignant hepatic stellate cells (a type of pericyte found in the liver and the major cell type involved in liver fibrosis) increased liver fibrosis and cirrhosis and increased transformation of adjacent epithelial cells into hepatocellular carcinoma. In the presence of functional p53, senescent stellate cells released factors that skewed macrophage polarization toward a tumor-inhibiting M1-state, whereas proliferating p53-deficient stellate cells secreted factors that polarized macrophages into a tumor-promoting M2-state and enhanced the proliferation of premalignant cells. Thus, p53 can also play a non–cell-autonomous role in suppressing tumor development by promoting an antitumor microenvironment in a damaged tissue. Cells of mesenchymal origin can drive this antitumor microenvironment by secreting factors that switch macrophage function.Remmers N, Anderson JM, Linde EM, Dimaio DJ, Lazenby AJ, Wandall HH, et al. Aberrant expression of mucin core proteins and o-linked glycans associated with progression of pancreatic cancer. Clin Cancer Res 2013;19:1981–93.Mucins are produced by epithelial cells and have a number of important functions, including protection, regulation of signal transduction, and generation of unique cellular microenvironments. Oncogenesis induces changes in expression of mucin core proteins and in their carbohydrate (glycan) modifications. These changes are thought to promote tumor progression and alter the immune response. Indeed, alterations in mucins and their glycans serve as useful biomarkers of disease. For example, CA125/MUC16 is a well-established biomarker for ovarian cancer, and the glycan structures Tn and STn are cancer-specific biomarkers. Remmers and colleagues simplify the complex world of mucins and glycans in pancreatic cancer and provide a comprehensive examination of their protein expression across the entire spectrum of disease, including tissue adjacent to neoplasia, high-grade pancreatic intraepithelial neoplasia (PanIN), malignant adenocarcinoma, and metastatic disease. To this end, the authors focused their study on tissue obtained from rapid autopsies on patients with pancreatic cancer. This method allowed for sampling of multiple anatomic regions, including the primary tumor and any metastatic lesions, at a single point in time. Most striking, in 14 of the 40 patients the authors were able to obtain tissue from the original surgical resection, allowing them to examine temporal progression, and in approximately half of these cases, progression from PanIN to malignant adenocarcinoma. Using this approach they were able to identify a field effect of cancer on adjacent pancreas with novel changes in MUC6 expression. MUC6 is normally expressed exclusively in pancreatic ducts; however, adjacent to pancreatic adenocarcinoma MUC6 is upregulated in the acini, consistent with acinar-to-ductal metaplasia. An interesting question that remains is whether these changes reflect a response to the local cancer or are preneoplastic lesions. By examining changes associated with tumor progression across a large number of patients, the authors have shown tumor-specific expression of novel glycopeptide structures and secreted mucins that may be useful as biomarkers of disease and therapeutic targets.Yu X, Guo C, Yi H, Qian J, Fisher PB, Subjeck JR, et al. A multifunctional chimeric chaperone serves as a novel immune modulator inducing therapeutic antitumor immunity. Cancer Res 2013;73:2093–103.Generation of a tumor-specific immune response is the ultimate goal of cancer immunotherapy, which can eradicate tumors without negatively affecting normal body functions. In this study, Yu and colleagues developed a unique chimeric immune chaperone complex called “Flagrp-170” containing glucose-regulated protein 170 (GRP170, HYOU1) and flagellin, a bacterial protein against which mammals often acquire an immune response. The vaccine was delivered thorough an adenoviral (Ad.) vector (Ad.Flagrp170) into mice bearing highly aggressive B16 melanoma cells, resulting in a profound reduction of tumor growth. Tumor growth inhibition was accompanied by release of Th1 cytokines IFN-γ and interleukin (IL)-2/12 and robust infiltration of cytotoxic CD8+ T cells. Mechanistically, Ad.Flagrp170 therapy augmented the generation of endogenous melanoma antigen-specific CD8+ T cells as well as CD8α+ dendritic cells (DC), the most professional antigen-presenting cells of the immune system, which in turn activated CD8+ T cells. The dependency of the CD8+ T cells for tumor eradication on the CD8α+ DCs was shown by depleting DCs from the melanoma tumor-bearing mice or Batf3−/− mice, deficient in CD8a+ DCs. In both cases, CD8+ T-cell function was impaired. On the other hand, depletion of CD8+ T cells, NK cells, IL-12, or IFN-γ also diminished the antitumor effect of the vaccine. Similar therapeutic efficacy was evident for Ad.Flagrp170 in mouse prostate and colon tumors. This promising multiarmed immune chaperone could be beneficial for immunotherapy in multiple cancers.Note: Breaking Advances are written by Cancer Research Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.